Telomeres consist of long TTAGGG nucleotide repeats and associated proteins at the ends of chromosomes that are essential to maintaining chromosomal integrity. We have shown that nucleotide diversity in genes coding for critical proteins in the telomere maintenance pathway is limited when compared with other types of genes. They are also highly conserved between species. Because these genes appear to be under tight genetic constraint, it is possible that germ-line genetic variation (i.e. single nucleotide polymorphisms, SNPs) in these genes could be a significant risk factor for cancer or other diseases.Further investigation into the population genetics and genetic variation of twelve genes critical in telomere maintenance has begun. These studies are based upon data generated in CGF's SNP 500 and SNP Diversity Panels, and will further define the world-wide genetic diversity and the extent of linkage disequilibrium of genes important in telomere biology. Methodological studies are underway to evaluate telomere length in diverse target tissues as determined by differing laboratory methods. These will form the basis for studies of germ-line genetic variants in genes critical in telomere biology as potential genetic markers for telomere length in healthy individuals and in individuals with cancer. Case-control studies of telomere length and cancer risk have been initiated, targeting populations with breast and prostate cancer. Our understanding of normal genetic variation in these genes will be used to identify new genes important in dyskeratosis congenita, an inherited bone marrow failure syndrome (IBMFS) characterized by abnormal nails, lacey reticular pigmentation, oral leukoplakia, short telomeres and significant risk of aplastic anemia. Through the NCIs IBMFS study, families with DC are evaluated for mutations known genes (DKC1, TERC and TERT) and those without a known mutation are studied further, using a variety of laboratory strategies aimed at finding new genes.